JP5686413B2 - Adamantanamine derivative - Google Patents

Description

  The present invention relates to an adamantaneamine derivative. Specifically, the present invention relates to an adamantaneamine derivative useful as an important intermediate of an 11βHSD-1 inhibitor (type I 11β hydroxysteroid dehydrogenase inhibitor) and a method for producing an 11βHSD-1 inhibitor using the same.

で示される化合物もしくはその塩またはそれらの溶媒和物は、１１βＨＳＤ−１阻害活性を有し、該化合物を含有する医薬組成物はＩＩ型糖尿病治療剤として有用であることが知られている（特許文献１、特許文献２）。
特許文献１には、上記化合物の製造方法として、実施例６９に以下の記載がある。

特許文献２には、上記化合物の製造方法として、実施例１に以下の記載がある。

特許文献２の実施例８４には、以下の製造方法が記載されている。

また、特許文献３には、式：

で示される化合物が記載されている。
しかし、これらの特許文献には、本発明の中間体、それを用いた式（ＩＩＩ）で示される化合物の製造方法は記載されていない。Formula (III):

Or a salt thereof or a solvate thereof has 11βHSD-1 inhibitory activity, and a pharmaceutical composition containing the compound is known to be useful as a therapeutic agent for type II diabetes (patent) Literature 1, Patent Literature 2).
Patent Document 1 includes the following description in Example 69 as a method for producing the above compound.

Patent Document 2 includes the following description in Example 1 as a method for producing the above compound.

In Example 84 of Patent Document 2, the following manufacturing method is described.

In addition, Patent Document 3 includes a formula:

Are described.
However, these patent documents do not describe the production method of the compound represented by the formula (III) using the intermediate of the present invention.

International Publication No. 2007/058346 Pamphlet International Publication No. 2008/142986 Pamphlet International Publication No. 2007/114125 Pamphlet

で示される化合物もしくはその塩またはそれらの溶媒和物を効率的に製造する上で有用な中間体を提供する。また、それら中間体を用いた式（ＩＩＩ）で示される化合物もしくはその塩またはそれらの溶媒和物の製造方法を提供する。Formula (III):

The present invention provides an intermediate useful for efficiently producing the compound represented by the formula (1) or a salt thereof or a solvate thereof. Moreover, the manufacturing method of the compound or its salt, or those solvates shown by Formula (III) using those intermediates is provided.

で示される化合物が、式（ＩＩＩ）で示される化合物の合成中間体として有用であることを見出した。本中間体を用いることにより、効率的に式（ＩＩＩ）で示される化合物を製造することができる。
先行技術記載の方法は、式（Ｖ）：

で示される化合物を製造した後に、アダマンタン骨格上の水酸基の修飾を行うものである。このルートは、多段階を経て製造された式（Ｖ）で示される化合物を原料としてさらに反応を行う必要があるので、その後の修飾反応の収率や最終目的物までのステップ数によっては、経済的ではない。
本発明のように先に所望の基を有するアダマンタンアミン誘導体を合成し、その後、式（Ｉ）：

で示される化合物と反応させることにより、式（ＩＩＩ）で示される化合物を効率よく製造することができることを見出した。The inventor has the formula (II):

Has been found to be useful as an intermediate for the synthesis of the compound represented by the formula (III). By using this intermediate, the compound represented by the formula (III) can be efficiently produced.
The method described in the prior art has the formula (V):

After the compound represented by formula (1) is produced, the hydroxyl group on the adamantane skeleton is modified. This route requires a further reaction using a compound represented by the formula (V) produced through multiple steps as a raw material, so depending on the yield of the subsequent modification reaction and the number of steps to the final product, Not right.
First, an adamantaneamine derivative having a desired group is synthesized as in the present invention, and then the formula (I):

It has been found that the compound represented by the formula (III) can be efficiently produced by reacting with the compound represented by the formula (III).

（式中、Ｒ^１０は、式：−（ＣＲ^１３Ｒ^１４）ｍ−ＮＲ^１２−Ｒ^１１（式中、Ｒ^１１は置換もしくは非置換のアシル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のスルファモイルであり、Ｒ^１２は水素または置換もしくは非置換のアルキルであり、Ｒ^１３およびＲ^１４はそれぞれ独立して水素、置換もしくは非置換のアルキルまたはハロゲンであり、ｍは０〜３の整数である。）で示される基、または
式：−（ＣＲ^１３Ｒ^１４）ｍ−Ｏ−Ｃ（Ｏ）−ＮＲ^１５−Ｒ^１６（式中、Ｒ^１５およびＲ^１６はそれぞれ独立して水素または置換もしくは非置換のアルキルであり、Ｒ^１３、Ｒ^１４およびｍは前記と同意義である。）で示される基である。）で示される化合物もしくはその塩またはそれらの溶媒和物。
（２）
ｍが０である、上記（１）記載の化合物もしくはその塩またはそれらの溶媒和物。
（３）
Ｒ^１０が式：−（ＣＲ^１３Ｒ^１４）ｍ−Ｏ−Ｃ（Ｏ）−ＮＲ^１５−Ｒ^１６で示される基である上記（１）または（２）記載の化合物もしくはその塩またはそれらの溶媒和物。
（４）
Ｒ^１０が式：−（ＣＲ^１３Ｒ^１４）ｍ−ＮＲ^１２−Ｒ^１１で示される基である上記（１）または（２）記載の化合物もしくはその塩またはそれらの溶媒和物。
（５）
式（Ｉ）：

（式中、Ｒ^１は式：−Ｙ−Ｒ^５（式中、Ｙは単結合、−Ｏ−または−Ｓ−であり、Ｒ^５は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基であり、
Ｒ^２およびＲ^３はそれぞれ独立して水素、置換もしくは非置換のアルキルまたはハロゲンであり、またはＲ^２およびＲ^３は隣接する炭素原子と一緒になって置換もしくは非置換の環を形成していてもよく、
Ｒ^４は式：−Ｃ（＝Ｏ）−ＮＲ^６Ｒ^７（ここでＲ^６およびＲ^７はそれぞれ独立して水素、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のヘテロサイクリル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアリールスルホニル、置換もしくは非置換のヘテロアリールスルホニルまたは置換もしくは非置換のヘテロサイクリルスルホニルであるか、またはＲ^６とＲ^７は隣接する窒素原子と一緒になって置換もしくは非置換の環を形成していてもよい。）で示される基、または
式：−ＮＲ^８Ｒ^９（ここでＲ^８およびＲ^９はそれぞれ独立して水素、カルボキシ、ヒドロキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のヘテロサイクリル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアリールスルホニル、置換もしくは非置換のアルキルオキシカルボニルまたは置換もしくは非置換のスルファモイルであるか、またはＲ^８とＲ^９は隣接する窒素原子と一緒になって置換もしくは非置換の環を形成していてもよい。）で示される基であり、
Ｘはヒドロキシまたは脱離基である。）で示される化合物を
式（ＩＩ）：

（式中、Ｒ^１０は上記（１）と同意義である。)で示される化合物と反応させることを特徴とする、式（ＩＩＩ）：

（式中、各記号は前記と同意義である。）で示される化合物もしくはその塩またはそれらの溶媒和物の製造方法。
（６）
Ｘがヒドロキシであり、縮合剤の存在下で反応させることを特徴とする、上記（５）記載の製造方法。
（７）
縮合剤が、Ｎ，Ｎ’−ジシクロヘキシルカルボジイミド、Ｎ，Ｎ’−ジイソプロピルカルボジイミドおよび1-エチル-3-（3-ジメチルアミノプロピル）カルボジイミド塩酸塩から選択される１以上のものである、上記（６）記載の製造方法。
（８）
１−ヒドロキシベンゾトリアゾールおよびＮ−ヒドロキシスクシンイミドから選択される１以上の添加剤の存在下で反応させることを特徴とする、上記（６）または（７）記載の製造方法。
（９）
式（ＩＶ）：

（式中、各記号は上記（５）と同意義である。）で示される化合物に、ハロゲン化剤を反応させ、
式（Ｉ）：

（式中、Ｘはハロゲンであり、Ｒ^１〜Ｒ^４は上記（５）と同意義である。）で示される化合物もしくはその塩またはそれらの溶媒和物を得る工程を含むものである、上記（５）記載の製造方法。
（１０）
ハロゲン化剤が、オキシ塩化リン、五塩化リン、オキザリルクロライド、塩化チオニルから選択されるものである、上記（９）記載の製造方法。
（１１）
式（Ｉ）で示される化合物と式（ＩＩ）で示される化合物を塩基の存在下で反応させることを特徴とする、上記（５）〜（１０）のいずれか１項に記載の製造方法。
なお、本明細書中、化合物を化合物と反応させることには、化合物もしくはその塩またはそれらの溶媒和物を化合物もしくはその塩またはそれらの溶媒和物と反応させることを包含する。The inventor has completed the following invention.
(1)
Formula (II):

(In the formula, R ¹⁰ represents the formula: — (CR ¹³ R ¹⁴ ) m—NR ¹² —R ¹¹ (wherein R ¹¹ represents substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted) Alkyloxycarbonyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl, R ¹² is hydrogen or substituted or unsubstituted alkyl, and R ¹³ and R ¹⁴ are each independently hydrogen, substituted or unsubstituted Substituted or alkyl, and m is an integer of 0 to 3.) or a group represented by the formula: — (CR ¹³ R ¹⁴ ) m—O—C (O) —NR ¹⁵ —R ¹⁶ (formula ^{among, R 15} and ^{R 16} are each independently hydrogen or a substituted or unsubstituted ^alkyl, R ^{13, R 14} and m are as defined above There.) Is a group represented by.) Compound or a salt thereof, or a solvate represented by.
(2)
The compound or a salt thereof, or a solvate thereof according to the above (1), wherein m is 0.
(3)
R ¹⁰ has the formula ^{:-( CR 13 R 14) m-} O-C (O) -NR 15 above is a group represented by ^{-R 16} (1) or (2) a compound according or a salt thereof, or a solvent Japanese products.
(4)
The compound or a salt thereof, or a solvate thereof according to the above (1) or (2), wherein R ¹⁰ is a group represented by the formula:-(CR ¹³ R ¹⁴ ) m-NR ¹² -R ¹¹ .
(5)
Formula (I):

(Wherein R ¹ represents the formula: —Y—R ⁵ (wherein Y represents a single bond, —O— or —S—, R ⁵ represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.) A group represented by
R ² and R ³ are each independently hydrogen, substituted or unsubstituted alkyl or halogen, or R ² and R ³ together with adjacent carbon atoms form a substituted or unsubstituted ring. Well,
R ⁴ has the formula: —C (═O) —NR ⁶ R ^7, where R ⁶ and R ⁷ are each independently hydrogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted Or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted heterocyclylsulfonyl, or R ⁶ and R ⁷ together with the adjacent nitrogen atom To form a substituted or unsubstituted ring. Groups represented or formula,: -NR 8 ^R 9 ^(wherein R ⁸ and R ⁹ are each independently hydrogen, carboxy, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, or substituted or unsubstituted sulfamoyl, or R ⁸ R ⁹ is a group represented by a nitrogen atom and may form a substituted or unsubstituted ring together.) Adjacent,
X is hydroxy or a leaving group. The compound represented by formula (II):

(Wherein R ¹⁰ has the same meaning as in the above (1)), which is reacted with a compound represented by formula (III):

(Wherein each symbol is as defined above), or a salt thereof, or a method for producing a solvate thereof.
(6)
X is hydroxy, and it makes it react in presence of a condensing agent, The manufacturing method of said (5) description characterized by the above-mentioned.
(7)
(6) wherein the condensing agent is one or more selected from N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ) Described production method.
(8)
The process according to (6) or (7) above, wherein the reaction is carried out in the presence of one or more additives selected from 1-hydroxybenzotriazole and N-hydroxysuccinimide.
(9)
Formula (IV):

(Wherein each symbol has the same meaning as in the above (5)), a halogenating agent is reacted,
Formula (I):

(Wherein X is a halogen, and R ^{1 to} R ⁴ are the same as defined in (5) above), or a salt thereof or a solvate thereof. ) Described production method.
(10)
The production method according to (9) above, wherein the halogenating agent is selected from phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, and thionyl chloride.
(11)
The method according to any one of (5) to (10) above, wherein the compound represented by the formula (I) is reacted with the compound represented by the formula (II) in the presence of a base.
In the present specification, reacting a compound with a compound includes reacting the compound or a salt thereof or a solvate thereof with the compound or a salt thereof or a solvate thereof.

  The compound represented by the formula (II) is useful as an intermediate for producing the compound represented by the formula (III). By using the intermediate of the present invention, the compound represented by the formula (III) can be efficiently produced.

（式中、Ｒ^１０は、式：−（ＣＲ^１３Ｒ^１４）ｍ−ＮＲ^１２−Ｒ^１１（式中、Ｒ^１１は置換もしくは非置換のアシル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のスルファモイルであり、Ｒ^１２は水素または置換もしくは非置換のアルキルであり、Ｒ^１３およびＲ^１４はそれぞれ独立して水素、置換もしくは非置換のアルキルまたはハロゲンであり、ｍは０〜３の整数である。）で示される基または、
式：−（ＣＲ^１３Ｒ^１４）ｍ−Ｏ−Ｃ（Ｏ）−ＮＲ^１５−Ｒ^１６（式中、Ｒ^１５およびＲ^１６はそれぞれ独立して水素または置換もしくは非置換のアルキルであり、Ｒ^１３、Ｒ^１４およびｍは前記と同意義である。）で示される基である。）で示される化合物は、以下のように製造することができる。Formula (II):

(In the formula, R ¹⁰ represents the formula: — (CR ¹³ R ¹⁴ ) m—NR ¹² —R ¹¹ (wherein R ¹¹ represents substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted) Alkyloxycarbonyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl, R ¹² is hydrogen or substituted or unsubstituted alkyl, and R ¹³ and R ¹⁴ are each independently hydrogen, substituted or unsubstituted A substituted alkyl or halogen, and m is an integer of 0 to 3.)
15 ^{-R 16} (wherein wherein ^{:-( CR 13 R 14) m-} O-C (O) -NR, R 15 and ^{R 16} are each independently hydrogen or a substituted or unsubstituted ^{alkyl, R 13} , R ¹⁴ and m are as defined above. ) Can be produced as follows.

（上記式中、式（ＩＩ−Ｘ）で示される化合物、式（ＩＩ−Ｙ）で示される化合物は、式（ＩＩ）で示される化合物を具体的に表したものである。）
化合物１は、国際公開第２００７／１１４１２５号パンフレット記載の化合物である。
化合物１を原料として、ヒドロキシ基を修飾し、当該修飾をした後に、アミノ保護基（フタルイミド基）をはずすことにより、式（ＩＩ−Ｘ）で示される化合物や式（ＩＩ−Ｙ）で示される化合物を製造することができる。
たとえば、化合物１に、濃硫酸の存在下でニトリル類を反応させることにより、Ｒ^１１が置換もしくは非置換のアルキルスルホニルである式（ＩＩ）で示される化合物を製造することができる。
化合物１にカルボニルジイミダゾールの存在下で、アミンを反応させることにより、Ｒ^１５およびＲ^１６がそれぞれ独立して水素または置換もしくは非置換のアルキルである式（ＩＩ）で示される化合物を製造することができる。
また、化合物１に各種イソシアネートを反応させることによって、Ｒ^１５およびＲ^１６がそれぞれ独立して水素、またはＲ^１５およびＲ^１６のいずれかが水素でもう一方が置換もしくは非置換のアルキルである式（ＩＩ）で示される化合物を製造することができる。
また、実施例３記載の方法に従って、化合物１から化合物５：

を合成し、遊離のアミノ基を修飾することにより、各種アミノ修飾体を合成し、その後フタルイミド基を脱保護して、式（ＩＩ）で示される化合物を製造してもよい。
たとえば、化合物５に各種アシルハライドを反応させ、その後フタルイミド基を脱保護することにより、Ｒ^１１が置換もしくは非置換のアシルである式（ＩＩ）で示される化合物を製造することができる。
化合物５に各種スルホニルハライド（たとえば、アルキルスルホニルハライド）を反応させ、その後フタルイミド基を脱保護することにより、Ｒ^１１が置換もしくは非置換のアルキルスルホニルである式（ＩＩ）で示される化合物を製造することができる。
化合物５にアルキルオキシカルボニルハライド（たとえば、クロロ炭酸メチルなど）を反応させ、その後フタルイミド基を脱保護することにより、Ｒ^１１が置換もしくは非置換のアルキルオキシカルボニルである式（ＩＩ）で示される化合物を製造することができる。
上記は例示であり、その他の式（ＩＩ）で示される化合物も、化合物１を原料として有機化学分野で知られている化学反応を行うことにより、製造することができる。
フタルイミド基の脱保護には、ヒドラジンやメチルヒドラジン等を用いることができる。溶媒としては、アルコールを用いることができる。本脱保護工程は、加熱還流下で行うことができる。
ｍ＝１の場合は、以下のように製造することができる。化合物１に３０％発煙硫酸及びギ酸を反応させ、ヒドロキシ基をカルボキシル基に変換し、メタノール中でアセチルクロライド等を反応させ、メチルエステル体に変換する。その後、エステルをリチウムボロハイドライド等で還元し、ヒドロキシメチル体を得る。当該ヒドロキシメチル体に各種の修飾を施し、ｍ＝０の場合と同様に化学反応を行い、ｍ＝１である式（ＩＩ）で示される化合物を製造することができる。
たとえば、上記ヒドロキシメチル体にクロロスルホニルイソシアナートを反応させ、その後フタルイミド基を脱保護することにより、カルバモイルオキシメチル体を得ることができる。
ｍ＝２の場合は、以下のように製造することができる。上記ヒドロキシメチル体のヒドロキシメチル基を−CH₂X (X=ハロゲン、Ms, Ts等の脱離基）とした後に、KCNまたはNaCNで処理することで−CH₂CNへと変換し、その後、加水分解して−CH₂CO₂Hとして、還元して−CH₂CH₂OHとする。その後、ｍ＝０の場合と同様に化学反応を行い、ｍ＝２である式（ＩＩ）で示される化合物を製造することができる。
ｍ＝３の場合は、以下のように製造することができる。上記−CH₂CH₂OH体を用いて、さらに上記と同様に処理し、−CH₂ CH₂CH₂OH体を製造し、その後、ｍ＝０の場合と同様に化学反応を行い、ｍ＝３である式（ＩＩ）で示される化合物を製造することができる。

(In the above formula, the compound represented by the formula (II-X) and the compound represented by the formula (II-Y) specifically represent the compound represented by the formula (II)).
Compound 1 is a compound described in International Publication No. 2007/114125 pamphlet.
The compound 1 is used as a raw material, the hydroxy group is modified, and after the modification, the amino protecting group (phthalimide group) is removed to obtain the compound represented by the formula (II-X) or the formula (II-Y). Compounds can be produced.
For example, a compound represented by the formula (II) in which R ¹¹ is a substituted or unsubstituted alkylsulfonyl can be produced by reacting compound 1 with nitriles in the presence of concentrated sulfuric acid.
Producing a compound of formula (II) wherein R ¹⁵ and R ¹⁶ are each independently hydrogen or substituted or unsubstituted alkyl by reacting compound 1 with an amine in the presence of carbonyldiimidazole. Can do.
Further, by reacting compound 1 with various isocyanates, R ¹⁵ and R ¹⁶ are each independently hydrogen, or one of R ¹⁵ and R ¹⁶ is hydrogen and the other is substituted or unsubstituted alkyl ( A compound represented by II) can be produced.
Also, according to the method described in Example 3, compound 1 to compound 5:

And modifying the free amino group to synthesize various amino modifications, and then deprotecting the phthalimide group to produce the compound represented by the formula (II).
For example, a compound represented by the formula (II) in which R ¹¹ is substituted or unsubstituted acyl can be produced by reacting compound 5 with various acyl halides and then deprotecting the phthalimide group.
A compound represented by the formula (II) in which R ¹¹ is a substituted or unsubstituted alkylsulfonyl is produced by reacting compound 5 with various sulfonyl halides (for example, alkylsulfonyl halide) and then deprotecting the phthalimide group. be able to.
A compound represented by the formula (II) in which R ¹¹ is substituted or unsubstituted alkyloxycarbonyl by reacting compound 5 with an alkyloxycarbonyl halide (eg, methyl chlorocarbonate) and then deprotecting the phthalimide group Can be manufactured.
The above is an example, and other compounds represented by the formula (II) can also be produced by performing a chemical reaction known in the field of organic chemistry using Compound 1 as a raw material.
Hydrazine, methyl hydrazine or the like can be used for deprotection of the phthalimide group. Alcohol can be used as the solvent. This deprotection step can be performed under heating and reflux.
In the case of m = 1, it can manufacture as follows. Compound 1 is reacted with 30% fuming sulfuric acid and formic acid to convert a hydroxy group to a carboxyl group, and to react with acetyl chloride or the like in methanol to convert it to a methyl ester form. Thereafter, the ester is reduced with lithium borohydride or the like to obtain a hydroxymethyl compound. Various modifications can be applied to the hydroxymethyl compound, and a chemical reaction can be performed in the same manner as in the case of m = 0 to produce a compound represented by the formula (II) in which m = 1.
For example, a carbamoyloxymethyl compound can be obtained by reacting the hydroxymethyl compound with chlorosulfonyl isocyanate and then deprotecting the phthalimide group.
In the case of m = 2, it can manufacture as follows. The hydroxymethyl group of the hydroxymethyl body -CH ₂ X after a (X = halogen, Ms, leaving group Ts, etc.), converted to -CH ₂ CN by treatment with KCN or NaCN, then, as -CH ₂ CO ₂ H by hydrolysis, and -CH ₂ CH ₂ OH by reduction. Thereafter, a chemical reaction is carried out in the same manner as in the case of m = 0, whereby a compound represented by the formula (II) in which m = 2 can be produced.
In the case of m = 3, it can manufacture as follows. Using the -CH ₂ CH ₂ OH form, the same treatment as above is carried out to produce a -CH ₂ CH ₂ CH ₂ OH form, and then a chemical reaction is carried out as in the case of m = 0, A compound of formula (II) which is 3 can be prepared.

（式中、Ｒ^１は式：−Ｙ−Ｒ^５（式中、Ｙは単結合、−Ｏ−または−Ｓ−であり、Ｒ^５は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のヘテロサイクリルである。）で示される基であり、
Ｒ^２およびＲ^３はそれぞれ独立して水素、置換もしくは非置換のアルキルまたはハロゲンであり、またはＲ^２およびＲ^３は隣接する炭素原子と一緒になって置換もしくは非置換の環を形成していてもよく、
Ｒ^４は式：−Ｃ（＝Ｏ）−ＮＲ^６Ｒ^７（ここでＲ^６およびＲ^７はそれぞれ独立して水素、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のヘテロサイクリル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアリールスルホニル、置換もしくは非置換のヘテロアリールスルホニルまたは置換もしくは非置換のヘテロサイクリルスルホニルであるか、またはＲ^６とＲ^７は隣接する窒素原子と一緒になって置換もしくは非置換の環を形成していてもよい。）で示される基、または
式：−ＮＲ^８Ｒ^９（ここでＲ^８およびＲ^９はそれぞれ独立して水素、カルボキシ、ヒドロキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のヘテロサイクリル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアリールスルホニル、置換もしくは非置換のアルキルオキシカルボニルまたは置換もしくは非置換のスルファモイルであるか、またはＲ^８とＲ^９は隣接する窒素原子と一緒になって置換もしくは非置換の環を形成していてもよい。）で示される基であり、
Ｘはヒドロキシまたは脱離基であり、
Ｒ^１０は、式：−（ＣＲ^１３Ｒ^１４）ｍ−ＮＲ^１２−Ｒ^１１（式中、Ｒ^１１は置換もしくは非置換のアシル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のスルファモイルであり、Ｒ^１２は水素または置換もしくは非置換のアルキルであり、Ｒ^１３およびＲ^１４はそれぞれ独立して水素、置換もしくは非置換のアルキルまたはハロゲンであり、ｍは０〜３の整数である。）で示される基、または
式：−（ＣＲ^１３Ｒ^１４）ｍ−Ｏ−Ｃ（Ｏ）−Ｎ（Ｒ^１５Ｒ^１６）（式中、Ｒ^１５およびＲ^１６はそれぞれ独立して水素または置換もしくは非置換のアルキルであり、Ｒ^１３、Ｒ^１４およびｍは前記と同意義である。）で示される基である。）A compound represented by the formula (III) can be produced using the compound represented by the formula (II) produced as described above.

(Wherein R ¹ represents the formula: —Y—R ⁵ (wherein Y represents a single bond, —O— or —S—, R ⁵ represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl.) A group represented by
R ² and R ³ are each independently hydrogen, substituted or unsubstituted alkyl or halogen, or R ² and R ³ together with adjacent carbon atoms form a substituted or unsubstituted ring. Well,
R ⁴ has the formula: —C (═O) —NR ⁶ R ^7, where R ⁶ and R ⁷ are each independently hydrogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted Or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted heterocyclylsulfonyl, or R ⁶ and R ⁷ together with the adjacent nitrogen atom To form a substituted or unsubstituted ring. Groups represented or formula,: -NR 8 ^R 9 ^(wherein R ⁸ and R ⁹ are each independently hydrogen, carboxy, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, or substituted or unsubstituted sulfamoyl, or R ⁸ R ⁹ is a group represented by a nitrogen atom and may form a substituted or unsubstituted ring together.) Adjacent,
X is hydroxy or a leaving group;
R ¹⁰ has the formula: — (CR ¹³ R ¹⁴ ) m—NR ¹² —R ¹¹ (wherein R ¹¹ is substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkyloxycarbonyl. Substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl, R ¹² is hydrogen or substituted or unsubstituted alkyl, and R ¹³ and R ¹⁴ are each independently hydrogen, substituted or unsubstituted alkyl or A group represented by formula: — (CR ¹³ R ¹⁴ ) m—O—C (O) —N (R ¹⁵ R ¹⁶ ) (wherein m is an integer of 0 to 3), R ¹⁵ and ^{R 16} are each independently hydrogen or a substituted or unsubstituted ^alkyl, R ^{13, R 14} and m are the same as defined above ) Is a group represented by the. )

This step is a step for producing a compound represented by the formula (III) by reacting a compound represented by the formula (I) with a compound represented by the formula (II).
When X is hydroxy, this step can be performed in the presence of a condensing agent.
As the condensing agent, an amide condensing agent used for condensation of a carboxyl group and an amino group can be used. For example, carbodiimides (eg, N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride), diphenyl phosphate azide, BOP reagent ( For example, BOP, PyBop, TBTU, etc.), DMT-MM, 1,1′-carbonylbis-1H-imidazole, 2-chloro1,3-dimethylimidazolium chloride, 4- (4,6-dimethoxy-1,3 , 5-triazin-2-yl) -4-methylmorpholinium chloride and the like. N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is preferable, and 1-ethyl-3- (3 is particularly preferable. -Dimethylaminopropyl) carbodiimide hydrochloride.
This step can be performed in the presence of an additive.
Examples of the additive include 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like. Particularly preferred is 1-hydroxybenzotriazole.
This step can be performed in the presence of a base. The base can be appropriately selected depending on the type of leaving group and the type of reaction solvent.
Examples of the base that can be used in this step include organic bases such as triethylamine, diisopropylethylamine, pyridine, imidazole, and diazabicycloundecene. Triethylamine, diisopropylethylamine, diazabicycloundecene and the like are preferable, and triethylamine is particularly preferable.
This step can be performed at -20 to 200 ° C. Preferably, it can carry out at 0-100 degreeC.
Examples of the reaction solvent include water, alcohols such as methanol, ethanol, and propanol, halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, dimethylformamide, dimethylacetamide, and 1-methyl. Aprotic polar solvents such as 2-pyrrolidone, ethers such as tetrahydrofuran and dioxane, acetonitrile, and the like can be used. Particularly preferred are dichloromethane and dimethylformamide.
The compound represented by the formula (I) and the compound represented by the formula (II) may be used in the form of a salt or a solvate.

（式中、Ｘはハロゲンであり、その他の記号は前記と同意義である。）
本工程は、式（ＩＶ）で示される化合物とハロゲン化剤を反応させ、式（Ｉ）で示される化合物を製造する工程である。
ハロゲン化剤としては、塩化チオニル、臭化チオニル、オキザリルクロライド、オキシ塩化リン、三塩化リン、五塩化リン、三臭化リン等があげられる。好ましくは、塩化チオニル、臭化ブロマイド、オキザリルクロライド、オキシ塩化リンであり、特に好ましくは塩化チオニルである。
本工程は、０〜１００℃で行うことができる。好ましくは、２０〜６０℃で行うことができる。
反応溶媒としては、テトラヒドロフラン、酢酸エチル、ジメチルホルムアミド等を用いることができる。特に好ましくはテトラヒドロフランである。
本工程終了後、式（Ｉ）で示される化合物を単離または非単離の状態で、式（ＩＩ）で示される化合物と反応させ、式（ＩＩＩ）で示される化合物を製造することができる。
なお、式（ＩV）で示される化合物は、塩や溶媒和物の形態で使用してもよい。

(Wherein X is halogen, and other symbols are as defined above.)
This step is a step for producing a compound represented by the formula (I) by reacting a compound represented by the formula (IV) with a halogenating agent.
Examples of the halogenating agent include thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide and the like. Preferred are thionyl chloride, bromide bromide, oxalyl chloride, and phosphorus oxychloride, and particularly preferred is thionyl chloride.
This step can be performed at 0 to 100 ° C. Preferably, it can carry out at 20-60 degreeC.
As the reaction solvent, tetrahydrofuran, ethyl acetate, dimethylformamide or the like can be used. Particularly preferred is tetrahydrofuran.
After completion of this step, the compound represented by formula (I) can be reacted with the compound represented by formula (II) in the isolated or non-isolated state to produce the compound represented by formula (III). .
The compound represented by the formula (IV) may be used in the form of a salt or solvate.

“Alkyl” means a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- Examples include butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Preferred is alkyl having 1 to 6 or 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso Examples include pentyl, neopentyl, n-hexyl, and isohexyl.

“Alkenyl” means a linear or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds to the above “alkyl”, and examples thereof include vinyl, 1-propenyl, 2 -Propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like.

“Alkynyl” means a linear or branched alkynyl having 2 to 8 carbon atoms having one or more triple bonds to the above “alkyl”, and examples thereof include ethynyl, propynyl, butynyl and the like. It is done.

“Aryl” means a monocyclic aromatic hydrocarbon group (eg, phenyl) and a polycyclic aromatic hydrocarbon group (eg, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1- Phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like. Preferably, phenyl or naphthyl (1-naphthyl, 2-naphthyl) is used.

“Heteroaryl” means monocyclic aromatic heterocyclic groups and fused aromatic heterocyclic groups.
The monocyclic aromatic heterocyclic group is an arbitrary substitutable substituent derived from a 5- to 8-membered aromatic ring which may contain 1 to 4 oxygen atoms, sulfur atoms and / or nitrogen atoms in the ring. Means a group which may have a bond at the position.
The condensed aromatic heterocyclic group has 1 to 4 5-8 aromatic rings, which may contain 1 to 4 oxygen atoms, sulfur atoms, and / or nitrogen atoms in the ring. It means a group which may have a bond at any substitutable position which is fused with a member aromatic carbocycle or other 5- to 8-membered aromatic heterocycle.

  Examples of the “heteroaryl” include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl). ), Imidazolyl (eg: 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg: 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg: 1,2,4-triazole-1-) Yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (eg 2- Oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg 3-isoxazolyl, 4-isoxazolyl, 5-i Xazolyl), thiazolyl (eg: 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (eg: 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (eg: 2-pyridyl, 3-pyridyl) 4-pyridyl), pyridazinyl (eg: 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg: 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanil (eg: 3-furazanyl), pyrazinyl (eg: 2 -Pyrazinyl), oxadiazolyl (eg 1,3,4-oxadiazol-2-yl), benzofuryl (eg 2-benzo [b] furyl, 3-benzo [b] furyl, 4-benzo [b] furyl 5-benzo [b] furyl, 6-benzo [b] furyl, 7-benzo [b] furyl), Zothienyl (eg 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [b] Thienyl), benzimidazolyl (eg, 1-benzimidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl), benzothiazolyl, dibenzofuryl, benzoxazolyl, quinoxalyl (eg, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl) ), Cinnolinyl (eg: 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolyl (eg: 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl) 7-quinazolinyl, 8 -Quinazolinyl), quinolyl (eg: 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (eg: 1-phthalazinyl, 5-phthalazinyl, 6 -Phthalazinyl), isoquinolyl (eg: 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), prill, pteridinyl (eg: 2-pteridinyl, 4-pteridinyl) , 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (eg 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (eg 1-indolyl), 2-indolyl, 3-indolyl, 4-i Drill, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, fanadinyl (eg 1-phenazinyl, 2-phenazinyl) or phenothiazinyl (eg 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl) and the like.

“Cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 15 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are mentioned.
“Cycloalkenyl” means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 15 carbon atoms, and examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and preferably cyclopropenyl, cyclobutenyl. , Cyclopentenyl and cyclohexenyl.

“Heterocyclyl” is a non-aromatic group that may contain 1 to 4 oxygen atoms, sulfur atoms, and / or nitrogen atoms in the ring, and may have a bond at any substitutable position. Means a heterocyclic group. Further, such a non-aromatic heterocyclic group may be further bridged with an alkyl chain having 1 to 4 carbon atoms, and a cycloalkane (preferably a 5- to 6-membered ring) or a benzene ring is condensed. Good. If it is non-aromatic, it may be saturated or unsaturated. Preferably it is a 5-8 membered ring. For example, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 2-morpholinyl, Examples are 3-morpholinyl, morpholino, tetrahydropyranyl.

“Halogen” includes fluorine, chlorine, bromine and iodine. Particularly preferred are chlorine, bromine and iodine.
“Substituted or unsubstituted ring formed together with adjacent carbon atoms” means a 3- to 8-membered ring, preferably a 4- to 6-membered ring. The ring may contain not only carbon atoms but also heteroatoms (oxygen atom, sulfur atom, nitrogen atom).
“Substituted or unsubstituted ring formed together with the adjacent nitrogen atom” means a 3- to 8-membered ring, preferably a 4- to 6-membered ring. The ring may contain not only a nitrogen atom but also a carbon atom and further a hetero atom (oxygen atom, sulfur atom, nitrogen atom).

“Acyl” refers to formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted Alternatively, it means unsubstituted heteroarylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl. “Alkylcarbonyl”, “alkenylcarbonyl”, “cycloalkylcarbonyl”, “cycloalkenylcarbonyl”, “arylcarbonyl”, “heteroarylcarbonyl”, “heterocyclylcarbonyl” “alkyl” moiety, “alkenyl” moiety, The “cycloalkyl” moiety, “cycloalkenyl” moiety, “aryl” moiety, “heteroaryl” moiety, and “heterocyclyl” moiety are the above “alkyl”, “alkenyl”, “cycloalkyl”, “cycloalkenyl”, respectively. ”,“ Aryl ”,“ heteroaryl ”,“ heterocyclyl ”.
Examples of the “leaving group” include alkyloxy, aryloxy, acyloxy, alkoxycarbonyloxy, arylcarbonyloxy, alkylsulfonyloxy, halogen and the like. In particular, halogen is preferable.

“Alkylsulfonyl”, “arylsulfonyl”, “heteroarylsulfonyl”, “heterocyclylsulfonyl”, “alkyl” moiety of “alkyloxycarbonyl”, “aryl” moiety, “heteroaryl” moiety, “heterocyclyl” The moieties are as defined above for “alkyl”, “aryl”, “heteroaryl”, and “heterocyclyl”.

“Substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted aryl”, “substituted heteroaryl”, “substituted cycloalkyl”, “substituted cycloalkenyl”, “substituted heterocyclyl” “adjacent carbon atoms” "Substituted ring formed together", "substituted amino", "substituted alkylsulfonyl", "substituted arylsulfonyl", "substituted heteroarylsulfonyl", "substituted heterocyclylsulfonyl", "adjacent nitrogen atom" Substituted ring "," substituted acyl "," substituted carbamoyl "," substituted thiocarbamoyl "," substituted alkyloxycarbonyl "," substituted sulfamoyl "," substituted alkylcarbonyl "," substituted Alkenylcarbonyl "," substituted cycloalkylcarbonyl "," substituted cycloalkenyl " Carbonyl ", as the substituent in the" substituted arylcarbonyl "," substituted heteroarylcarbonyl "," substituted heterocyclyl carbonyl ", e.g.,
Halogen, hydroxy, carboxy, nitro, cyano,
Substituted or unsubstituted alkyl (substituents are halogen, hydroxy, carboxy, cyano, amino, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, alkyloxycarbonyl, alkyloxycarbonylamino, carbamoyl, eg methyl , ethyl, isopropyl, tert- _{butyl, CF 3, CH 2 OH,} CH 2 CH 2 OH, CH 2 COOCH 3, CH 2 NH 2, CH 2 CN, benzyl),
Substituted or unsubstituted alkenyl (substituents are halogen, carboxy, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, eg vinyl),
Substituted or unsubstituted alkynyl (substituents are halogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, eg ethynyl),
Substituted or unsubstituted aryl (substituents are halogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, substituted or unsubstituted heterocyclyloxy, such as phenyl, naphthyl),
Substituted or unsubstituted cycloalkyl (substituents are halogen, cyano, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, alkyloxycarbonyl, eg cyclopropyl, cyclobutyl),
Substituted or unsubstituted cycloalkenyl (substituents are halogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, eg, cyclopropenyl),
Substituted or unsubstituted heteroaryl (substituents are halogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, eg, tetrazolyl, indolyl, pyrazolyl),
Substituted or unsubstituted heterocyclyl (substituents are halogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidyl),
Substituted or unsubstituted alkyloxy (halogen, carboxy, cyano, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl. Examples: methoxy, ethoxy, propoxy, butoxy, OCF ₃ ),
Substituted or unsubstituted aryloxy (substituents are halogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, eg, phenyloxy),
Substituted or unsubstituted silyloxy,
Substituted or unsubstituted amino (eg, alkylamino (eg, methylamino, ethylamino, dimethylamino), acylamino (eg, acetylamino, benzoylamino), arylalkylamino (eg, benzylamino, tritylamino), hydroxyamino Alkylaminoalkyl (eg, diethylaminomethyl), alkyloxycarbonylamino, alkylsulfonylamino, carbamolylamino, heterocyclylcarbonylamino, arylsulfonylamino, heteroarylsulfonylamino),
Substituted or unsubstituted carbamoyl (Substituents are hydroxy, cyano, substituted or unsubstituted alkyl, alkyloxy, alkylsulfonyl. Examples: alkylcarbamoyl (example: methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, phenylethylcarbamoyl, dimethyl) Aminoethylcarbamoyl, isopropylcarbamoyl, hydroxyethylcarbamoyl), alkylsulfonylcarbamoyl, heteroarylalkylcarbamoyl, substituted or unsubstituted alkyloxycarbamoyl).
Substituted or unsubstituted carbamoyloxy (substituents are halogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl),
Substituted or unsubstituted acyl (substituents are halogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl. Examples: alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, formyl, acetyl) ,
Substituted or unsubstituted alkylsulfonyl (substituents include halogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, such as methanesulfonyl, ethanesulfonyl),
Substituted or unsubstituted arylsulfonyl,
Substituted or unsubstituted heteroarylsulfonyl (substituents are halogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl),
Substituted or unsubstituted sulfamoyl,
Substituted or unsubstituted alkyloxycarbonyl (substituents are halogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, eg methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), aryloxycarbonyl, heteroaryl Oxycarbonyl, heterocyclyloxycarbonyl,
Cycloalkylsulfonyl, heteroarylsulfonyl, heterocyclylsulfonyl,
Alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclylsulfinyl,
Nitroso,
Alkenyloxy (eg vinyloxy, allyloxy),
Arylalkyloxy (eg benzyloxy),
Azide,
Isocyanato, isocyanato, thiocyanato, isothiocyanato, mercapto,
Alkylthio (eg methylthio),
Examples include groups selected from the group consisting of formyloxy, haloformyl, oxalolo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, ureido, amidino, guanidino, phthalimide, oxo and the like. It may be substituted with 1 to 4 such substituents.

One or more hydrogen, carbon or other atoms of the compounds of the present invention may be replaced with hydrogen, carbon or other isotopes of atoms.
For example, the compound of formula (II) includes all radiolabels of the compound of formula (II). Such “radiolabeled”, “radiolabeled” and the like of the compound of formula (II) are each encompassed by the present invention and are useful as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays. . Examples of isotopes that can be incorporated into the compound of formula (II) of the present invention include ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, and ³⁵ S, respectively. , ¹⁸ F, and ³⁶ Cl include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. The radiolabeled compound of the present invention can be prepared by methods well known in the art. For example, a tritium-labeled compound of formula (II) can be prepared by introducing tritium into a specific compound of formula (II), for example, by a catalytic dehalogenation reaction using tritium. This method involves reacting a compound of formula (II) with a suitably halogen-substituted precursor and tritium gas in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base. May be. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ^{The 14} C-labeled compound can be prepared by using a raw material having ¹⁴ C carbon.

The “salt” includes the following salts.
Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and strontium salt; metal salts such as beryllium salt, magnesium salt, zinc salt and transition metal salt; ammonium salt ; Aliphatic amine salts such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt; N, N-dibenzylethylenediamine, venetamine Aralkylamine salts such as salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, isoquinoline salts; tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltols Examples include quaternary ammonium salts such as liethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, and tetrabutylammonium salt; basic amino acid salts such as arginine salt and lysine salt.
Examples of the acid salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate, ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate; Acidic amino acids such as aspartate and glutamate are included.

  “Solvate” means a solvate of a compound or a salt thereof, and examples thereof include alcohol (eg, ethanol) solvate and hydrate. Examples of the hydrate include monohydrate, dihydrate and the like.

Examples of R ¹⁰ include the formula: — (CR ¹³ R ¹⁴ ) m—NR ¹² —R ¹¹ or the formula: — (CR ¹³ R ¹⁴ ) m—O—C (O) —NR ¹⁵ —R ¹⁶ .
R ¹¹ includes substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl. Preferred are substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkyloxycarbonyl.
R ¹² includes hydrogen or substituted or unsubstituted alkyl. Preferably, it is hydrogen.
R ¹³ and R ¹⁴ each independently include hydrogen, substituted or unsubstituted alkyl, or halogen. Preferably, it is hydrogen.
R ¹⁵ and R ¹⁶ each independently include hydrogen or substituted or unsubstituted alkyl.
m is an integer of 0-3. Preferably, it is 0 or 1. Particularly preferred is 0.

R ¹ is of the formula: —Y—R ⁵ .
Y is a single bond, —O— or —S—. -O- is preferable.
R ⁵ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl, substituted or unsubstituted heterocyclyl. Preferably, it is a substituted or unsubstituted alkyl.
R ² and R ³ are each independently hydrogen, substituted or unsubstituted alkyl or halogen. R ² and R ³ may be combined with adjacent carbon atoms to form a substituted or unsubstituted ring. Preferred as R ² and R ³ is substituted or unsubstituted alkyl.
Examples of R ⁴ include a group represented by the formula: —C (═O) —NR ⁶ R ⁷ or a formula: —NR ⁸ R ⁹ . Preferably, it is a group represented by the formula: —NR ⁸ R ⁹ .
R ⁶ and R ⁷ are each independently hydrogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or Examples include unsubstituted heteroarylsulfonyl or substituted or unsubstituted heterocyclylsulfonyl. R ⁶ and R ⁷ may be combined with an adjacent nitrogen atom to form a substituted or unsubstituted ring.
Preferred as R ⁶ and R ⁷ is hydrogen.
R ⁸ and R ⁹ are each independently hydrogen, carboxy, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted Or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, or substituted or unsubstituted sulfamoyl. R ⁸ and R ⁹ may be combined with an adjacent nitrogen atom to form a substituted or unsubstituted ring.
Preferred as R ⁸ and R ⁹ are hydrogen, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted acyl.
X is hydroxy or a leaving group.

以下に実施例を挙げて本発明を説明するが、本発明を実施例に限定するものではない。
なお、各化合物については、ＮＭＲまたはｌｏｇ ｋ’の測定結果を示した。
ここで、ｌｏｇ ｋ’とは親油性の程度を表す値であり、以下の式により算出される。
ｌｏｇ ｋ’＝ｌｏｇ（ｔ_Ｒ−ｔ_０）／ｔ_０
ｔ_Ｒ：グラジエント条件下における化合物の保持時間
ｔ_０：カラムに保持されない標準物質の保持時間
測定にはＸＴｅｒｒａ ＭＳ Ｃ１８ ５μｍ、２．１×１００ｍｍのカラム（Ｗａｔｅｒｓ製）を使用し、流速０．２５ｍＬ／分でアセトニトリル／ｐＨ６．８ｂｕｆｆｅｒ（５：９５〜９５：５／２０分）の直線勾配をかけて測定した。As the compound represented by the formula (II), the following compounds are preferable.

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to the examples.
In addition, about each compound, the measurement result of NMR or log k 'was shown.
Here, log k ′ is a value representing the degree of lipophilicity and is calculated by the following equation.
log k ′ = log (t _R −t ₀ ) / t ₀
t _R : retention time of compound under gradient conditions t ₀ : XTerra MS C18 5 μm, 2.1 × 100 mm column (Waters) was used for measuring the retention time of the standard substance not retained on the column, and the flow rate was 0.25 mL. It was measured by applying a linear gradient of acetonitrile / pH 6.8 buffer (5:95 to 95: 5/20 minutes) per minute.

化合物１は、国際公開第２００７／１１４１２５号パンフレット記載の方法に順じて製造した。
化合物１（１．６ｇ）をジクロロメタン（６ｍｌ）、アセトニトリル（３ｍｌ）にけん濁し０℃に冷却した。濃硫酸（１．１ｇ）を滴下し０℃で２０分撹拌後、室温で１４時間撹拌した。反応終了後、冷却した飽和炭酸水素ナトリウム水溶液に注ぎ、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物２（１．５５ｇ，８５．１％）を得た。
NMR(d6-DMSO); δ(ppm)1.50-1.53 (m, 2H), 1.77 (s, 3H), 1.94-2.03 (m, 5H), 2.12-2.18 (m, 4H), 2.68 (br s, 2H), 4.19 (s, 1H), 7.39 (s, 1H), 7.82 (s, 4H).

Compound 1 was produced according to the method described in International Publication No. 2007/114125 pamphlet.
Compound 1 (1.6 g) was suspended in dichloromethane (6 ml) and acetonitrile (3 ml) and cooled to 0 ° C. Concentrated sulfuric acid (1.1 g) was added dropwise, stirred at 0 ° C. for 20 minutes, and then stirred at room temperature for 14 hours. After completion of the reaction, the mixture was poured into a cooled saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 2 (1.55 g, 85.1%).
NMR (d6-DMSO); δ (ppm) 1.50-1.53 (m, 2H), 1.77 (s, 3H), 1.94-2.03 (m, 5H), 2.12-2.18 (m, 4H), 2.68 (br s, 2H), 4.19 (s, 1H), 7.39 (s, 1H), 7.82 (s, 4H).

化合物２（１．５５ｇ）のエタノール懸濁液（１６ｍｌ）にメチルヒドラジン（０．６１ｍｌ）を加え、２８時間加熱還流を行った。反応終了後、溶媒を留去し、残渣に２Ｎ塩酸水溶液と酢酸エチルを加えて撹拌後、不溶物をろ過した。分液し、水層を酢酸エチルで洗浄し、減圧下に濃縮した。５Ｎ水酸化ナトリウム水溶液を加えてアルカリ性とした後に、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、アミンＩＩ−１を得た。
NMR(d6-DMSO); δ(ppm)1.24-1.28 (m, 2H), 1.69-1.99 (m, 14H), 2.86 (s, 1H), 7.25 (s, 1H)

Methylhydrazine (0.61 ml) was added to an ethanol suspension (16 ml) of compound 2 (1.55 g), and the mixture was heated to reflux for 28 hours. After completion of the reaction, the solvent was distilled off, 2N aqueous hydrochloric acid and ethyl acetate were added to the residue and the mixture was stirred and insoluble matter was filtered off. The layers were separated, and the aqueous layer was washed with ethyl acetate and concentrated under reduced pressure. 5N Aqueous sodium hydroxide solution was added to make the solution alkaline, followed by extraction with dichloromethane. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to give amine II-1.
NMR (d6-DMSO); δ (ppm) 1.24-1.28 (m, 2H), 1.69-1.99 (m, 14H), 2.86 (s, 1H), 7.25 (s, 1H)

化合物１（１．５ｇ）をジクロロメタン（６ｍｌ）、プロピオニトリル（３ｍｌ）にけん濁し０℃に冷却した。濃硫酸（９９０ｍｇ）を滴下し、室温で１８時間撹拌した。反応終了後、冷却した飽和炭酸水素ナトリウム水溶液に注ぎ、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物３（１．１７ｇ，６５．８％）を得た。

Compound 1 (1.5 g) was suspended in dichloromethane (6 ml) and propionitrile (3 ml) and cooled to 0 ° C. Concentrated sulfuric acid (990 mg) was added dropwise and stirred at room temperature for 18 hours. After completion of the reaction, the mixture was poured into a cooled saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 3 (1.17 g, 65.8%).

化合物３（１．１７ｇ）のエタノール縣濁液（１２ｍｌ）にメチルヒドラジン（４４２μｌ）を加え、２４時間加熱還流を行った。反応終了後、溶媒を留去し、残渣に２Ｎ塩酸水溶液と酢酸エチルを加えて撹拌後、不溶物をろ過した。分液し、水層を酢酸エチルで洗浄し、減圧下に濃縮した。２Ｎ水酸化ナトリウム水溶液を加えてアルカリ性とした後に、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、アミンＩＩ−２（６６０ｍｇ，８９．４％）を得た。
NMR(d6-DMSO); δ(ppm)0.93 (t, J = 7.6 Hz, 3H), 1.25-1.28 (m, 2H), 1.69 (br s, 2H), 1.87-2.02 (m, 11H), 2.86 (s, 1H), 7.16 (s, 1H)

Methylhydrazine (442 μl) was added to an ethanol suspension (12 ml) of compound 3 (1.17 g), and the mixture was heated to reflux for 24 hours. After completion of the reaction, the solvent was distilled off, 2N aqueous hydrochloric acid and ethyl acetate were added to the residue and the mixture was stirred and insoluble matter was filtered off. The layers were separated, and the aqueous layer was washed with ethyl acetate and concentrated under reduced pressure. A 2N aqueous sodium hydroxide solution was added to make the mixture alkaline, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to give amine II-2 (660 mg, 89.4%).
NMR (d6-DMSO); δ (ppm) 0.93 (t, J = 7.6 Hz, 3H), 1.25-1.28 (m, 2H), 1.69 (br s, 2H), 1.87-2.02 (m, 11H), 2.86 (s, 1H), 7.16 (s, 1H)

化合物１（２．０ｇ）をジクロロメタン（７ｍｌ）、クロロアセトニトリル（３．５ｍｌ）にけん濁し０℃に冷却した。濃硫酸（９９０ｍｇ）を滴下し、室温で６．５時間撹拌した。反応終了後、冷却した飽和炭酸水素ナトリウム水溶液に注ぎ、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物４（２．３７ｇ，９４．５％）を得た。
NMR(d6-DMSO); δ(ppm)1.52-1.55 (m, 2H), 1.96-2.19 (m, 9H), 2.71 (br s, 2H), 3.98 (s, 2H), 4.20 (s, 1H), 7.77 (s, 1H), 7.82 (s, 4H)

Compound 1 (2.0 g) was suspended in dichloromethane (7 ml) and chloroacetonitrile (3.5 ml) and cooled to 0 ° C. Concentrated sulfuric acid (990 mg) was added dropwise, and the mixture was stirred at room temperature for 6.5 hours. After completion of the reaction, the mixture was poured into a cooled saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 4 (2.37 g, 94.5%).
NMR (d6-DMSO); δ (ppm) 1.52-1.55 (m, 2H), 1.96-2.19 (m, 9H), 2.71 (br s, 2H), 3.98 (s, 2H), 4.20 (s, 1H) , 7.77 (s, 1H), 7.82 (s, 4H)

化合物４（２．３７ｇ）のエタノール溶液（１３ｍｌ）に酢酸（２．６ｍｌ）、チオウレア（５８１ｍｇ）を加え、１４時間加熱還流を行った。反応終了後、水を加え、生じた不溶物をろ過した。ろ液に５Ｎ水酸化ナトリウム水溶液を加えてアルカリ性とした後に、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、化合物５（１．３３ｇ）を得た。精製することなく次の反応に用いた。

Acetic acid (2.6 ml) and thiourea (581 mg) were added to an ethanol solution (13 ml) of compound 4 (2.37 g), followed by heating under reflux for 14 hours. After completion of the reaction, water was added and the resulting insoluble material was filtered. The filtrate was made alkaline by adding 5N aqueous sodium hydroxide solution, and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to obtain Compound 5 (1.33 g). Used in the next reaction without purification.

化合物５（１．３３ｇ）のジクロロメタン溶液（１５ｍｌ）にトリエチルアミン（１．２６ｍｌ）を加え、０℃に冷却した後、メタンスルホニルクロリド（４１８μｌ）を加えた。室温にて１．５時間撹拌し、反応終了後、有機層を１Ｎ塩酸水溶液で洗浄した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物６（９０７ｍｇ，５３．７％）を得た。
NMR(d6-DMSO); δ(ppm)1.49-1.52 (m, 2H), 1.93-2.15 (m, 9H), 2.72 (br s, 2H), 3.34 (s, 3H), 4.16 (s, 1H), 6.93 (s, 1H), 7.82 (s, 4H)

Triethylamine (1.26 ml) was added to a dichloromethane solution (15 ml) of compound 5 (1.33 g), and after cooling to 0 ° C., methanesulfonyl chloride (418 μl) was added. The mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the organic layer was washed with 1N aqueous hydrochloric acid. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 6 (907 mg, 53.7%).
NMR (d6-DMSO); δ (ppm) 1.49-1.52 (m, 2H), 1.93-2.15 (m, 9H), 2.72 (br s, 2H), 3.34 (s, 3H), 4.16 (s, 1H) , 6.93 (s, 1H), 7.82 (s, 4H)

化合物６（９０７ｍｇ）のエタノール懸濁液（２０ｍｌ）にメチルヒドラジン（３２２μｌ）を加え、一晩加熱還流を行った。反応終了後、溶媒を留去し、残渣に２Ｎ塩酸水溶液、酢酸エチルとヘキサンの１：１混合液を加えて撹拌後、不溶物をろ過した。分液し、水層をエーテルで洗浄した。５Ｎ水酸化ナトリウム水溶液を加えてアルカリ性とした後に、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、アミンＩＩ−３（３２１ｍｇ，５４．２％）を得た。
NMR(d6-DMSO); δ(ppm)1.23-1.26 (m, 2H), 1.71-1.99 (m, 11H), 2.84 (s, 1H), 2.92 (s, 3H), 6.76 (br s, 1H)

Methylhydrazine (322 μl) was added to an ethanol suspension (20 ml) of compound 6 (907 mg), and the mixture was heated to reflux overnight. After completion of the reaction, the solvent was distilled off, and a 2N aqueous hydrochloric acid solution and a 1: 1 mixture of ethyl acetate and hexane were added to the residue. After stirring, the insoluble material was filtered off. The layers were separated and the aqueous layer was washed with ether. 5N Aqueous sodium hydroxide solution was added to make the solution alkaline, followed by extraction with dichloromethane. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to give amine II-3 (321 mg, 54.2%).
NMR (d6-DMSO); δ (ppm) 1.23-1.26 (m, 2H), 1.71-1.99 (m, 11H), 2.84 (s, 1H), 2.92 (s, 3H), 6.76 (br s, 1H)

化合物５（７００ｍｇ）のジクロロメタン溶液（１４ｍｌ）にトリエチルアミン（０．９９ｍｌ）を加え、０℃に冷却した後、クロロギ酸メチル（２７２μｌ）を加えた。室温にて４時間撹拌し、反応終了後、０．５Ｎ塩酸水溶液に注いだ。ジクロロメタンで抽出し、有機層を飽和食塩水で洗浄した。硫酸ナトリウムで乾燥後、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物７（２６６ｍｇ，３１．８％）を得た。
NMR(d6-DMSO); δ(ppm)1.49-1.52 (m, 2H), 1.89-2.16 (m, 9H), 2.68 (br s, 2H), 3.49 (s, 3H), 4.16 (s, 1H), 6.92 (s, 1H), 7.82 (s, 4H)

Triethylamine (0.99 ml) was added to a dichloromethane solution (14 ml) of compound 5 (700 mg), cooled to 0 ° C., and then methyl chloroformate (272 μl) was added. The mixture was stirred at room temperature for 4 hours. The mixture was extracted with dichloromethane, and the organic layer was washed with saturated brine. After drying with sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 7 (266 mg, 31.8%).
NMR (d6-DMSO); δ (ppm) 1.49-1.52 (m, 2H), 1.89-2.16 (m, 9H), 2.68 (br s, 2H), 3.49 (s, 3H), 4.16 (s, 1H) , 6.92 (s, 1H), 7.82 (s, 4H)

化合物７（２５９ｍｇ）のエタノール懸濁液（３ｍｌ）にメチルヒドラジン（９７μｌ）を加え、２４時間加熱還流を行った。反応終了後、溶媒を留去し、残渣に２Ｎ塩酸水溶液を加え、不溶物をろ過した。水層を酢酸エチルで洗浄し、５Ｎ水酸化ナトリウム水溶液を加えてアルカリ性とした後に、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、アミンＩＩ−４（１３５ｍｇ，８２．４％）を得た。
NMR(d6-DMSO); δ(ppm)1.23-1.26 (m, 2H), 1.69-1.99 (m, 11H), 2.84 (s, 1H), 3.45 (s, 3H), 6.76 (s, 1H)

Methylhydrazine (97 μl) was added to an ethanol suspension (3 ml) of compound 7 (259 mg), and the mixture was heated to reflux for 24 hours. After completion of the reaction, the solvent was distilled off, 2N hydrochloric acid aqueous solution was added to the residue, and insoluble matter was filtered off. The aqueous layer was washed with ethyl acetate, made alkaline with 5N aqueous sodium hydroxide solution, and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to give amine II-4 (135 mg, 82.4%).
NMR (d6-DMSO); δ (ppm) 1.23-1.26 (m, 2H), 1.69-1.99 (m, 11H), 2.84 (s, 1H), 3.45 (s, 3H), 6.76 (s, 1H)

化合物１（５．０ｇ）のジクロロメタン溶液（５０ｍｌ）に１，１−カルボニルジイミダゾール（３．２７ｇ）、４−ジメチルアミノピリジン（４１１ｍｇ）を加え、室温にて１４時間撹拌した。原料の消失を確認した後に、ジメチルアミン（２５．２ｍｌ，２Ｍテトラヒドロフラン溶液）を滴下し、更に室温で１０時間撹拌した。反応終了後、２Ｎ塩酸水溶液を加えて酸性とし、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物８（２．７３ｇ，４４．１％）を得た。
NMR(d6-DMSO);δ(ppm)1.48-1.57(m,2H),2.060-2.29(m,9H),2.72-2.86(m,8H),4.18-4.22(br,1H), 7.82(s,4H)

1,1-carbonyldiimidazole (3.27 g) and 4-dimethylaminopyridine (411 mg) were added to a dichloromethane solution (50 ml) of compound 1 (5.0 g), and the mixture was stirred at room temperature for 14 hours. After confirming disappearance of the raw materials, dimethylamine (25.2 ml, 2M tetrahydrofuran solution) was added dropwise, and the mixture was further stirred at room temperature for 10 hours. After completion of the reaction, the mixture was acidified with 2N aqueous hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 8 (2.73 g, 44.1%).
NMR (d6-DMSO); δ (ppm) 1.48-1.57 (m, 2H), 2.060-2.29 (m, 9H), 2.72-2.86 (m, 8H), 4.18-4.22 (br, 1H), 7.82 (s , 4H)

化合物８（１．０ｇ）のエタノール溶液（１０ｍｌ）にメチルヒドラジン（３６１μｌ）を加え、２０時間加熱還流を行った。反応終了後、溶媒を留去し、残渣に２Ｎ塩酸水溶液と酢酸エチルを加えて撹拌後、分液した。水層を酢酸エチルで洗浄し、減圧下に濃縮した。炭酸ナトリウム水溶液を加えてアルカリ性とした後に、析出した固体をろ取した。水洗後、乾燥し、アミンＩＩ−５（５００ｍｇ，７７．３％）を得た。
NMR(CDCl₃); δ(ppm)1.42-1.51(m,2H),1.88-2.19(m,11H),2.85(s,6H),3.05-3.10(br,1H)

Methylhydrazine (361 μl) was added to an ethanol solution (10 ml) of compound 8 (1.0 g), followed by heating under reflux for 20 hours. After completion of the reaction, the solvent was distilled off, 2N aqueous hydrochloric acid and ethyl acetate were added to the residue, and the mixture was stirred and separated. The aqueous layer was washed with ethyl acetate and concentrated under reduced pressure. After adding an aqueous sodium carbonate solution to make it alkaline, the precipitated solid was collected by filtration. After washing with water and drying, amine II-5 (500 mg, 77.3%) was obtained.
NMR (CDCl ₃ ); δ (ppm) 1.42-1.51 (m, 2H), 1.88-2.19 (m, 11H), 2.85 (s, 6H), 3.05-3.10 (br, 1H)

化合物１（２．０ｇ）のトルエン溶液（２０ｍｌ）にエチルイソシアネート（２．７ｍｌ）を加え、８．５時間加熱還流を行った。反応終了後、溶媒を留去し、得られた固体をジイソプロピルエーテルで洗浄した。乾燥し、化合物９（２．１５ｇ，８６．７％）を得た。
NMR(d6-DMSO);δ(ppm)0.99(t,J=7.2Hz,3H),1.47-1.57(m,2H),2.04-2.32(m,9H),2.76-2.84(br,2H),2.88-3.00(m,2H),4.17-4.22(br,1H),6.84-6.91(m,1H),7.83(s,4H)

Ethyl isocyanate (2.7 ml) was added to a toluene solution (20 ml) of compound 1 (2.0 g), and the mixture was heated to reflux for 8.5 hours. After completion of the reaction, the solvent was distilled off, and the resulting solid was washed with diisopropyl ether. Drying gave compound 9 (2.15 g, 86.7%).
NMR (d6-DMSO); δ (ppm) 0.99 (t, J = 7.2 Hz, 3H), 1.47-1.57 (m, 2H), 2.04-2.32 (m, 9H), 2.76-2.84 (br, 2H), 2.88-3.00 (m, 2H), 4.17-4.22 (br, 1H), 6.84-6.91 (m, 1H), 7.83 (s, 4H)

化合物９（１．０ｇ）のエタノール溶液（１０ｍｌ）にメチルヒドラジン（３６１μｌ）を加え、２５時間加熱還流を行った。反応終了後、溶媒を留去し、残渣に２Ｎ塩酸水溶液と酢酸エチルを加えて撹拌後、分液した。水層を酢酸エチルで洗浄し、減圧下に濃縮した。炭酸ナトリウム水溶液を加えてアルカリ性とした後に、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をジイソプロピルエーテルで洗浄し、乾燥した後にアミンＩＩ−６（４７５ｍｇ，７３．４％）を得た。
NMR(CDCl₃);δ(ppm)1.11(t,J=7.2Hz,3H),1.38-1.51(m,2H),1.87-2.18(m,11H),3.03-3.21(m,3H),4.42-4.59(br,1H)

Methylhydrazine (361 μl) was added to an ethanol solution (10 ml) of compound 9 (1.0 g), and the mixture was heated to reflux for 25 hours. After completion of the reaction, the solvent was distilled off, 2N aqueous hydrochloric acid and ethyl acetate were added to the residue, and the mixture was stirred and separated. The aqueous layer was washed with ethyl acetate and concentrated under reduced pressure. A sodium carbonate aqueous solution was added to make the solution alkaline, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was washed with diisopropyl ether and dried to give amine II-6 (475 mg, 73.4%).
_{NMR (CDCl 3); δ (} ppm) 1.11 (t, J = 7.2Hz, 3H), 1.38-1.51 (m, 2H), 1.87-2.18 (m, 11H), 3.03-3.21 (m, 3H), 4.42 -4.59 (br, 1H)

化合物１（２．５ｇ）のテトラヒドロフラン溶液（５０ｍｌ）を−３０℃に冷却し、クロロスルホニルイソシアナート（１．５ｍｌ）を加え、−３０℃で１時間攪拌した。次に炭酸水素ナトリウム（３．５ｇ）、水（１ｍｌ）を加え、室温にて１６時間攪拌した。クロロホルムで抽出し、有機層を飽和食塩水で洗浄した。硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をジイソプロピルエーテルで洗浄し、乾燥した後に化合物１０（２．７３ｇ，９５．５％）を得た。
NMR(d6-DMSO);δ(ppm)1.46-1.58(m,2H),2.02-2.30(m,9H),2.76-2.84(br,2H),4.16-4.22(br,1H),6.10-6.35(m,1H),7.82(s,4H)

A tetrahydrofuran solution (50 ml) of compound 1 (2.5 g) was cooled to −30 ° C., chlorosulfonyl isocyanate (1.5 ml) was added, and the mixture was stirred at −30 ° C. for 1 hour. Next, sodium hydrogen carbonate (3.5 g) and water (1 ml) were added, and the mixture was stirred at room temperature for 16 hours. Extraction was performed with chloroform, and the organic layer was washed with saturated brine. It dried with sodium sulfate and the solvent was distilled off. The residue was washed with diisopropyl ether and dried to give compound 10 (2.73 g, 95.5%).
NMR (d6-DMSO); δ (ppm) 1.46-1.58 (m, 2H), 2.02-2.30 (m, 9H), 2.76-2.84 (br, 2H), 4.16-4.22 (br, 1H), 6.10-6.35 (m, 1H), 7.82 (s, 4H)

化合物１０（１．０ｇ）のエタノール溶液（１０ｍｌ）にメチルヒドラジン（３９１μｌ）を加え、２１時間加熱還流を行った。反応終了後、溶媒を留去し、残渣に２Ｎ塩酸水溶液と酢酸エチルを加えて撹拌後、分液した。水層を酢酸エチルで洗浄し、減圧下に濃縮した。炭酸ナトリウム水溶液を加えてアルカリ性とした後に、析出した固体をろ取した。水洗後、乾燥し、アミンＩＩ−７（４６８ｍｇ，７５．７％）を得た。
NMR(d6-DMSO);δ(ppm)1.40-1.51(m,2H),1.91-2.22(m,11H),3.28-3.34(br,1H),6.06-6.42(br,2H),8.08-8.34(br,2H)

Methylhydrazine (391 μl) was added to an ethanol solution (10 ml) of compound 10 (1.0 g), and the mixture was heated to reflux for 21 hours. After completion of the reaction, the solvent was distilled off, 2N aqueous hydrochloric acid and ethyl acetate were added to the residue, and the mixture was stirred and separated. The aqueous layer was washed with ethyl acetate and concentrated under reduced pressure. After adding an aqueous sodium carbonate solution to make it alkaline, the precipitated solid was collected by filtration. After washing with water and drying, amine II-7 (468 mg, 75.7%) was obtained.
NMR (d6-DMSO); δ (ppm) 1.40-1.51 (m, 2H), 1.91-2.22 (m, 11H), 3.28-3.34 (br, 1H), 6.06-6.42 (br, 2H), 8.08-8.34 (br, 2H)

化合物ＩＶ−１は、国際公開第２００７／０５８３４６号パンフレットの実施例３２の化合物３３をアルカリ条件で加水分解して製造した。
化合物ＩＶ−１(３００ｍｇ)のジメチルホルムアミド溶液（６．０ｍｌ）にアミンＩＩ−１（２５４ｍｇ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩（WSCD HCl）（２５４ｍｇ）、１−ヒドロキシベンゾトリアゾール（HOBt）（４１ｍｇ）、トリエチルアミン（２１２μｌ）を加え、室温にて１４時間攪拌した。反応終了後、２Ｎ塩酸水溶液に注ぎ、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物ＩＩＩ−１ (２４４ｍｇ，４９．５％)を得た。
NMR(d6-DMSO);δ(ppm)0.98(d,J=6.8Hz,6H),1.27(s,6H),1.42(d,J=12.4Hz,2H),1.75(s,3H),1.93-2.03(m,12H),3.93(brs,1H),4.10(d,J=6.4Hz,2H),6.37(d,J=14.4Hz,1H),6.81(d,J=14.0Hz,1H),6.92(brs,1H),7.14(brs,1H),7.35(s,1H),7.41(d,J=6.4Hz,1H),7.98(s,1H)

Compound IV-1 was produced by hydrolyzing compound 33 of Example 32 of International Publication No. 2007/058346 pamphlet under alkaline conditions.
To a solution of compound IV-1 (300 mg) in dimethylformamide (6.0 ml), amine II-1 (254 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (WSCD HCl) (254 mg), 1 -Hydroxybenzotriazole (HOBt) (41 mg) and triethylamine (212 μl) were added, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the mixture was poured into 2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain compound III-1 (244 mg, 49.5%).
NMR (d6-DMSO); δ (ppm) 0.98 (d, J = 6.8Hz, 6H), 1.27 (s, 6H), 1.42 (d, J = 12.4Hz, 2H), 1.75 (s, 3H), 1.93 -2.03 (m, 12H), 3.93 (brs, 1H), 4.10 (d, J = 6.4Hz, 2H), 6.37 (d, J = 14.4Hz, 1H), 6.81 (d, J = 14.0Hz, 1H) , 6.92 (brs, 1H), 7.14 (brs, 1H), 7.35 (s, 1H), 7.41 (d, J = 6.4Hz, 1H), 7.98 (s, 1H)

化合物ＩＶ−２は、国際公開第２００７／０５８３４６号パンフレットの実施例２９記載の化合物２０のCO₂tBu基を酸性条件下で加水分解し、カルボン酸を得、当該カルボン酸をDPPA/Et₃Nで処理して、イソシアネート体に変換し、ついでメタノールを反応させ、その後にCO₂Et基をアルカリ条件下で加水分解して、製造した。（DPPAは、ジフェニルホスフォリルアジド）
化合物ＩＶ−２(１００ｍｇ)のジメチルホルムアミド溶液（２．０ｍｌ）にアミンＩＩ−２（８２ｍｇ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩（８８ｍｇ）、１−ヒドロキシベンゾトリアゾール（１２ｍｇ）、トリエチルアミン（８６μｌ）を加え、室温にて一晩攪拌した。反応終了後、０．５Ｎ塩酸水溶液に注ぎ、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物ＩＩＩ−２ (１４５ｍｇ，８９．０％)を得た。
ｌｏｇｋ’＝０．９０９

Compound IV-2 is obtained by hydrolyzing the CO ₂ tBu group of Compound 20 described in Example 29 of WO 2007/058346 under acidic conditions to obtain a carboxylic acid, which is converted to DPPA / Et ₃ N The product was converted to an isocyanate form by treatment with methanol, and then reacted with methanol, and then the CO ₂ Et group was hydrolyzed under alkaline conditions to produce. (DPPA is diphenylphosphoryl azide)
To a solution of compound IV-2 (100 mg) in dimethylformamide (2.0 ml), amine II-2 (82 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (88 mg), 1-hydroxybenzotriazole (12 mg) and triethylamine (86 μl) were added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the mixture was poured into a 0.5N hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain compound III-2 (145 mg, 89.0%).
logk ′ = 0.909

化合物ＩＶ−２(２００ｍｇ)のジメチルホルムアミド溶液（４．０ｍｌ）にアミンＩＩ−３（１５１ｍｇ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩（１５３ｍｇ）、１−ヒドロキシベンゾトリアゾール（２５ｍｇ）、トリエチルアミン（１２８μｌ）を加え、室温にて3日間攪拌した。反応終了後、２Ｎ塩酸水溶液に注ぎ、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物ＩＩＩ−３ (３１０ｍｇ，９１．４％)を得た。
NMR(d6-DMSO);δ(ppm)0.97(d,J=6.4Hz,6H),1.38-1.42(m,8H),1.89-2.05(m,12H),2.92(s,3H),3.49(s,3H),3.91(brs,1H),4.08(d,J=6.4Hz,2H),6.30(d,J=14.4Hz,1H),6.79(d,J=14.0Hz,1H),6.87(s,1H),7.25(s,1H),7.44(d,J=6.0Hz,1H),7.96(s,1H)

A solution of compound IV-2 (200 mg) in dimethylformamide (4.0 ml) with amine II-3 (151 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (153 mg), 1-hydroxybenzotriazole (25 mg) and triethylamine (128 μl) were added, and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the mixture was poured into 2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain compound III-3 (310 mg, 91.4%).
NMR (d6-DMSO); δ (ppm) 0.97 (d, J = 6.4Hz, 6H), 1.38-1.42 (m, 8H), 1.89-2.05 (m, 12H), 2.92 (s, 3H), 3.49 ( s, 3H), 3.91 (brs, 1H), 4.08 (d, J = 6.4Hz, 2H), 6.30 (d, J = 14.4Hz, 1H), 6.79 (d, J = 14.0Hz, 1H), 6.87 ( s, 1H), 7.25 (s, 1H), 7.44 (d, J = 6.0Hz, 1H), 7.96 (s, 1H)

化合物ＩＶ−３は、国際公開第２００７／０５８３４６号パンフレットの実施例３０の化合物２９に記載されている。
化合物ＩＶ−３(８０ｍｇ)のジクロロメタン溶液（２．０ｍｌ）にアミンＩＩ−４（６４ｍｇ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩（６５ｍｇ）、１−ヒドロキシベンゾトリアゾール（１１ｍｇ）、トリエチルアミン（５４μｌ）を加え、室温にて一晩攪拌した。反応終了後、０．５Ｎ塩酸水溶液に注ぎ、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物ＩＩＩ−４ (１００ｍｇ，７５．０％)を得た。
ｌｏｇｋ’＝０．８８６

Compound IV-3 is described in compound 29 of Example 30 of WO 2007/058346 pamphlet.
Compound IV-3 (80 mg) in dichloromethane (2.0 ml) was added to amine II-4 (64 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (65 mg), 1-hydroxybenzotriazole ( 11 mg) and triethylamine (54 μl) were added and stirred overnight at room temperature. After completion of the reaction, the mixture was poured into 0.5N hydrochloric acid aqueous solution and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain compound III-4 (100 mg, 75.0%).
logk ′ = 0.886

化合物ＩＶ−３(８０ｍｇ)のジクロロメタン溶液（３．２ｍｌ）にアミンＩＩ−８（７４ｍｇ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩（WSCD）（６５ｍｇ）、１−ヒドロキシベンゾトリアゾール（HOBt）（１１ｍｇ）、トリエチルアミン（９０μｌ）を加え、室温にて３６時間攪拌した。反応終了後、０．５Ｎ塩酸水溶液に注ぎ、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物ＩＩＩ−５ (９８ｍｇ，７３．８％)を得た。
ｌｏｇｋ’＝０．８３８

Compound IV-3 (80 mg) in dichloromethane solution (3.2 ml) was added to amine II-8 (74 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (WSCD) (65 mg), 1-hydroxy. Benzotriazole (HOBt) (11 mg) and triethylamine (90 μl) were added, and the mixture was stirred at room temperature for 36 hours. After completion of the reaction, the mixture was poured into 0.5N hydrochloric acid aqueous solution and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain compound III-5 (98 mg, 73.8%).
logk ′ = 0.838

化合物ＩＶ−４は、国際公開第２００８／１４２９８６号パンフレットの実施例８４の化合物ＩＩ−１８を用いた。
化合物ＩＶ−４(１００ｍｇ)のジメチルホルムアミド溶液（２．０ｍｌ）にアミンＩＩ−５（８９ｍｇ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩（７８ｍｇ）、１−ヒドロキシベンゾトリアゾール（１２．６ｍｇ）、トリエチルアミン（１０８μｌ）を加え、室温にて２３時間攪拌した。反応終了後、２Ｎ塩酸水溶液に注ぎ、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物ＩＩＩ−６ (１５５ｍｇ，９１．７％)を得た。
NMR(d6-DMSO);δ(ppm)1.40(s,8H),1.88-2.14(m,11H),2.77(s,6H),3.49(s,3H),3.93-4.00(m,1H),6.57(d,J=13.8Hz,1H),6.88(d,J=13.8Hz,1H),7.36(s,1H),7.96(s,1H),8.34(d,J=7.2Hz,1H)

As compound IV-4, compound II-18 of Example 84 in WO2008 / 142986 pamphlet was used.
A solution of compound IV-4 (100 mg) in dimethylformamide (2.0 ml) with amine II-5 (89 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (78 mg), 1-hydroxybenzotriazole (12.6 mg) and triethylamine (108 μl) were added, and the mixture was stirred at room temperature for 23 hours. After completion of the reaction, the mixture was poured into 2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain compound III-6 (155 mg, 91.7%).
NMR (d6-DMSO); δ (ppm) 1.40 (s, 8H), 1.88-2.14 (m, 11H), 2.77 (s, 6H), 3.49 (s, 3H), 3.93-4.00 (m, 1H), 6.57 (d, J = 13.8Hz, 1H), 6.88 (d, J = 13.8Hz, 1H), 7.36 (s, 1H), 7.96 (s, 1H), 8.34 (d, J = 7.2Hz, 1H)

化合物ＩＶ−４(１００ｍｇ)のジメチルホルムアミド溶液（２．０ｍｌ）にアミンＩＩ−６（８９ｍｇ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩（７８ｍｇ）、１−ヒドロキシベンゾトリアゾール（１２．６ｍｇ）、トリエチルアミン（１０８μｌ）を加え、室温にて２０時間攪拌した。反応終了後、２Ｎ塩酸水溶液に注ぎ、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物ＩＩＩ−７ (１２２ｍｇ，７２．２％)を得た。
NMR(d6-DMSO);δ(ppm)0.98(t,J=6.9Hz,3H),1.40(s,8H),1.88-2.13(m,11H),2.88-2.97(m,2H),3.49(s,3H),3.93-3.99(m,1H),6.57(d,J=13.8Hz,1H),6.81-6.92(m,2H),7.34(s,1H),7.96(s,1H),8.33(d,J=6.6Hz,1H)

A solution of compound IV-4 (100 mg) in dimethylformamide (2.0 ml) with amine II-6 (89 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (78 mg), 1-hydroxybenzotriazole (12.6 mg) and triethylamine (108 μl) were added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the mixture was poured into 2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain compound III-7 (122 mg, 72.2%).
NMR (d6-DMSO); δ (ppm) 0.98 (t, J = 6.9 Hz, 3H), 1.40 (s, 8H), 1.88-2.13 (m, 11H), 2.88-2.97 (m, 2H), 3.49 ( s, 3H), 3.93-3.99 (m, 1H), 6.57 (d, J = 13.8Hz, 1H), 6.81-6.92 (m, 2H), 7.34 (s, 1H), 7.96 (s, 1H), 8.33 (d, J = 6.6Hz, 1H)

化合物ＩＶ−４(１００ｍｇ)のジメチルホルムアミド溶液（２．０ｍｌ）にアミンＩＩ−７（７９ｍｇ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩（７８ｍｇ）、１−ヒドロキシベンゾトリアゾール（１２．６ｍｇ）、トリエチルアミン（１０８μｌ）を加え、室温にて１４時間攪拌した。反応終了後、２Ｎ塩酸水溶液に注ぎ、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物ＩＩＩ−８ (１３７ｍｇ，８５．６％)を得た。
NMR(d6-DMSO);δ(ppm)1.40(s,8H),1.88-2.13(m,11H),3.50(s,3H),3.94-3.99(m,1H),6.05-6.35(s,2H),6.58(d,J=13.6Hz,1H),6.88(d,J=13.6Hz,1H),7.35(s,1H),7.96(s,1H),8.33(d,J=6.8Hz,1H)

A solution of compound IV-4 (100 mg) in dimethylformamide (2.0 ml) with amine II-7 (79 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (78 mg), 1-hydroxybenzotriazole (12.6 mg) and triethylamine (108 μl) were added, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the mixture was poured into 2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain compound III-8 (137 mg, 85.6%).
NMR (d6-DMSO); δ (ppm) 1.40 (s, 8H), 1.88-2.13 (m, 11H), 3.50 (s, 3H), 3.94-3.99 (m, 1H), 6.05-6.35 (s, 2H ), 6.58 (d, J = 13.6Hz, 1H), 6.88 (d, J = 13.6Hz, 1H), 7.35 (s, 1H), 7.96 (s, 1H), 8.33 (d, J = 6.8Hz, 1H) )

  The compound represented by the formula (II) is useful as an intermediate for producing the compound represented by the formula (III). By using the intermediate of the present invention, the compound represented by the formula (III) can be efficiently produced.

Claims (9)

Formula (II):

(Wherein R ¹⁰ is a group represented by the formula : — (CR ¹³ R ¹⁴ ) m—O—C (O) —NR ¹⁵ —R ¹⁶ , wherein R ¹³ and R ¹⁴ are each independently hydrogen, substituted or non- alkyl or halogen-substituted, m is an integer of 0 to 3, R ¹⁵ and R ¹⁶ are each independently hydrogen or substituted or unsubstituted alkyl der of Ru.) a group represented by.) in Or a solvate thereof. The compound according to claim 1, wherein m is 0, or a salt thereof, or a solvate thereof. Formula (I):

(Wherein R ¹ represents the formula: —Y—R ⁵ (wherein Y represents a single bond, —O— or —S—, R ⁵ represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.) A group represented by
R ² and R ³ are each independently hydrogen, substituted or unsubstituted alkyl or halogen, or R ² and R ³ together with adjacent carbon atoms form a substituted or unsubstituted ring. Well,
R ⁴ has the formula: —C (═O) —NR ⁶ R ^7, where R ⁶ and R ⁷ are each independently hydrogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted Or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted heterocyclylsulfonyl, or R ⁶ and R ⁷ together with the adjacent nitrogen atom To form a substituted or unsubstituted ring. Groups represented or formula,: -NR 8 ^R 9 ^(wherein R ⁸ and R ⁹ are each independently hydrogen, carboxy, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, or substituted or unsubstituted sulfamoyl, or R ⁸ R ⁹ is a group represented by a nitrogen atom and may form a substituted or unsubstituted ring together.) Adjacent,
X is hydroxy or a leaving group. The compound represented by formula (II):

(Wherein R ¹⁰ has the same meaning as in claim 1), and is reacted with a compound represented by formula (III):

(Wherein each symbol is as defined above), or a salt thereof, or a method for producing a solvate thereof. The process according to claim 3 , wherein X is hydroxy and the reaction is carried out in the presence of a condensing agent. Condensing agent, those N, N'- dicyclohexylcarbodiimide, N, 1 or more selected from N'- diisopropylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, according to claim 4 The manufacturing method as described. Characterized in that the reaction in the presence of one or more additives selected from 1-hydroxybenzotriazole and N- hydroxysuccinimide, claim 4 or 5 method according. Formula (IV):

(Wherein each symbol has the same meaning as in claim 3 ), a halogenating agent is reacted with the compound,
Formula (I):

Is intended to include the step of obtaining a compound or a salt thereof, or a solvate represented by (wherein, X is halogen, R ¹ to R ⁴ are as defined in claim 3.), According to claim 3, wherein Manufacturing method. The production method according to claim 7 , wherein the halogenating agent is selected from phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, and thionyl chloride. The method according to any one of claims 3 to 8 , wherein the compound represented by the formula (I) is reacted with the compound represented by the formula (II) in the presence of a base.